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Metaplasticity: tuning synapses

and networks for plasticity
Wickliffe C. Abraham
Abstract | Synaptic plasticity is a key component of the learning machinery in the brain. It is
vital that such plasticity be tightly regulated so that it occurs to the proper extent at the
proper time. Activity-dependent mechanisms that have been collectively termed
metaplasticity have evolved to help implement these essential computational constraints.
Various intercellular signalling molecules can trigger lasting changes in the ability of
synapses to express plasticity; their mechanisms of action are reviewed here, along with a
consideration of how metaplasticity might affect learning and clinical conditions.

Long-term potentiation
(LTP). A long-lasting and
activity-dependent increase in
synaptic efficacy. Canonically it
requires activation of the
NMDAR subtype of glutamate
receptors; however, different
forms of LTP caused by the
activation of other receptor
subtypes also occur.
Long-term depression
(LTD). The converse of LTP: in
LTD there is a long-lasting and
activity-dependent decrease in
synaptic efficacy.
Excitotoxicity
Cellular toxicity involving the
activation of glutamate
receptors in the CNS. Excessive
activation of these receptors
by high concentrations of
glutamate or by neurotoxins
leads to cell death.
Tetanus
A bout of HFS used to elicit
activity-dependent synaptic
plasticity. The frequency and
duration of the stimulation
varies across protocols.
Department of Psychology
and the Brain Health and
Repair Research Centre,
University of Otago, BOX 56,
Dunedin, 9054, New Zealand.
e-mail:
cabraham@psy.otago.ac.nz
doi:10.1038/nrn2356
Published online 10 April 2008
The ability of neurons to modify their structure and
function as a result of activity is critical for normal devel-
opment, learning and responding to brain damage and
neurological disease. At the synaptic level, neural activity
can generate persistent forms of synaptic plasticity, such
as long-term potentiation (LTP) and long-term depression
(LTD). There is now a wealth of data indicating that LTP
and LTD mechanisms are used to retain new informa-
tion in activated networks of neurons1,2. Safeguards must
therefore be in place to prevent the saturation of LTP
or LTD, which could ultimately compromise the ability
of networks to discriminate events and store informa-
tion and, in the case of extreme levels of LTP, lead to
excitotoxicity.
How is the proper balance of LTP and LTD main-
tained? Various intercellular signalling molecules
— including catecholamines, GABA (γ-aminobutyric
acid), acetylcholine, cytokines and hormones — directly
regulate the degree of LTP and LTD that can be induced.
However, a different kind of regulation that persists
across time also exists. Here, neural activity at one point
in time can change cells or synapses such that their abil-
ity to exhibit LTP or LTD after a later bout of activity
is altered. This form of plasticity regulation has been
termed metaplasticity3,4. The ‘meta’ part of the term
reflects the higher-order nature of the plasticity — that
is, the plasticity of synaptic plasticity.
Essentially, metaplasticity entails a change in the
physiological or biochemical state of neurons or syn-
apses that alters their ability to generate synaptic plas-
ticity. A key feature of metaplasticity is that this change
outlasts the triggering (priming) bout of activity and
persists at least until a second bout of activity induces
LTP or LTD (BOX 1). This distinguishes metaplasticity
from more conventional forms of plasticity modulation
in which the modulating and regulated events overlap in
time. Metaplasticity entails an extensive range of mecha-
nisms, many of which overlap with the mechanisms of
conventional plasticity. This overlap, plus the fact that
plasticity and metaplasticity can be induced simultane-
ously, poses a considerable challenge for metaplasticity
research in terms of experimental design and interpreta-
tion. Nonetheless, there has been substantial progress
in understanding metaplasticity over the past decade.
In this Review, paradigms for inducing metaplasticity
and other associated mechanisms will be detailed, fol-
lowed by a consideration of the behavioural and clinical
implications of these processes.
NMDA-receptor-mediated metaplasticity
A common paradigm for experimentally inducing
metaplasticity involves pharmacological or synaptic
activation of NMDA (N‑methyl‑d-aspartate) receptors
(NMDARs). NMDAR activation is a key trigger for LTP
induction; however, it has also been shown to trigger
metaplastic changes that inhibit subsequent induction
of LTP5–8 (FIG. 1a). This effect is restricted to the activated
synapses and slowly decays over 60–90 minutes5. The
capacity to induce LTP can be recovered by increas-
ing the tetanus stimulus intensity, indicating that the
NMDAR priming stimulation elevates the threshold
for LTP rather than completely inhibiting it5. However,
even when LTP is induced by strong or repeated tetanic
stimulation, priming synaptic activity can inhibit its per-
sistence8,9. The inhibition of LTP by priming synaptic
activity depends on the activation of NMDARs, adeno-
sine A2 receptors, p38 mitogen-activated protein kinase
(p38 MAPK) and the protein phosphatases 1A, 2A and
calcineurin8–11. Importantly, the inhibition of LTP can-
not be explained as simply a saturation of potentiation

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Box 1 | Methodological considerations in metaplasticity research

The standard paradigm for studying metaplasticity is to Metaplasticity
have an episode of priming activity at one point in time and Metaplasticity Synaptic plasticity
then a subsequent plasticity-inducing event, such as low-
frequency stimulation (LFS), high-frequency stimulation
(Minutes to days)
(HFS) or learning, that evokes synaptic plasticity such as
long-term potentiation (LTP) or long-term depression (LTD). Priming activity HFS/LFS
The priming signal can entail electrical stimulation of neural Neurotransmitters, Learning
activity, pharmacological activation of specific transmitter paracrine signals,
receptors, or behavioural events that might cause hormone hormones, etc.
release in addition to neural activity. An essential aspect of
Plasticity modulation
this protocol is that there must be a change in neural Synaptic plasticity
function as a result of the priming that persists after the
termination or washout of the priming stimulus and that
alters the response to a subsequent plasticity-inducing
event (see figure, top). This distinguishes metaplasticity Neurotransmitters, HFS/LFS
from conventional modulation of plasticity, whereby the paracrine signals, Learning
modulation occurs in conjunction with the induction of hormones, etc.
plasticity (see figure, bottom). There is no agreed criterion
for the degree of persistence that is required to meet the
definition of metaplasticity, but commonly studied effects have ranged from minutes to many days. Nature Reviews | Neuroscience
The study of metaplasticity is facilitated when the priming stimulation does not overtly alter the strength of synaptic
transmission, but instead changes only the state of readiness of synapses to generate LTP or LTD later on. If the priming
stimulation does cause, for example, LTP, this makes it ambiguous whether a lack of further LTP induction by an HFS is due
to a ceiling for LTP having been reached (termed saturation) or due to the mechanisms that generate LTP being actively
inhibited. The situation also becomes ambiguous if such priming facilitates subsequent response depression, because it
then needs to be ascertained whether LTD is being facilitated183 or whether the synapses have simply become capable of
exhibiting depotentiation184. Because LTD and depotentiation entail at least partially dissociable mechanisms185, it greatly
simplifies the analysis of LTD priming if prior LTP has not been induced and therefore depotentiation is not possible.
Unfortunately for investigators, it is probable that bouts of neural activity often cause both synaptic plasticity and
metaplasticity. Protocols that induce LTP can also trigger metaplastic mechanisms that inhibit further LTP34, and LFS can
evoke a metaplastic lowering of the LTD threshold early in the stimulus train that is necessary for LTD induction16. This
can complicate the interpretation of molecular correlates of plasticity, such as gene expression and protein synthesis,
because in principle these events might be critical for synaptic plasticity, metaplasticity or both.

Uncaging
The release of a molecule from
a photolabile binding partner
known as a cage. Cages
typically inhibit the biological
activity of the bound (‘caged’)
molecule. A brief flash of light
of the appropriate wavelength
can photochemically disrupt
the structure of the binding
partner and render the now
uncaged molecule biologically
active.
processes by the priming stimulation12, as it can occur
even when the priming stimulation does not cause any
detectable change in basal synaptic transmission5,8,13.
NMDAR activation can also facilitate the subsequent
induction of LTD14 (FIG. 1a). The LTD facilitation can be
generated by low-frequency priming stimulation14,15, is
restricted to the activated synapses and lasts for 60–90
minutes in vitro16 (it lasts longer in vivo14). The effect of
priming on LTD can occur rapidly enough to contribute
to the induction of LTD by conventional low-frequency
stimulation (LFS) protocols16. Again, the priming stimu-
lation can facilitate LTD without itself causing persistent
synaptic plasticity.
The expression mechanisms that underlie NMDAR-
mediated metaplasticity are not well understood. It has
been reported that prior induction of LTP reduces the
postsynaptic voltage threshold for subsequent LTD
and elevates it for further LTP17, but it is not clear
what mechanisms mediate these effects or whether
similar changes occur following non-plasticity-inducing
priming stimulation.
It has been suggested that NMDAR activation results
in LTD of NMDAR currents (LTDNMDAR), which are
crucial for the induction of conventional LTD and LTP
and are known to be highly plastic in their function and
localization (for reviews, see Refs 18,19). In support of
this hypothesis, both LFS and low-frequency uncaging
of glutamate at single dendritic spines cause LTDNMDAR
and a reduction in Ca2+ entry through the receptor chan-
nels20–22. Both nitric oxide (NO) and protein kinase C
(PKC) mediate the LTDNMDAR. These findings are sup-
ported by the fact that NMDAR activation increases
NO production, which can in turn suppress NMDAR
currents23,24, and by the fact that pharmacological acti-
vation of PKC by phorbol esters causes a dispersal of
NMDARs from synaptic to extrasynaptic sites25,26, which
might also be a prelude to receptor endocytosis19,27. Both
NO and PKC have been linked to NMDAR-mediated
metaplasticity23,28–31, as has p38 MAPK31,32.
Despite the attractiveness of this hypothesis, there is
no direct evidence that LTDNMDAR mediates metaplastic
inhibition of LTP. Furthermore, other mechanisms are
almost certainly involved. For example, the apparently
NMDAR-dependent saturation of LTP by repeated high-
frequency stimulation (HFS) protocols actually reflects
an inhibition of further LTP, which can be recovered by
using stronger stimuli during the HFS33, by waiting for the
metaplasticity to decay34 or by stimulating β-adrenergic
receptors35. This form of metaplasticity is not mediated
by NO or by a reduction in NMDAR currents35.
Downstream of NMDAR activation there are many
other potential sites of metaplasticity expression. Ca2+-
dependent kinases and phosphatases are central to plas-
ticity processes, and priming stimulation could alter the

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a Figure 1 | Glutamate-receptor-mediated mechanisms of

+ LTP metaplasticity. a | The black (control) line shows how
synaptic strength changes in response to afferent activity at
different levels of postsynaptic cell firing at excitatory
Change in synaptic strength

synapses on hippocampal CA1 pyramidal cells. θLTD and θLTP

represent the threshold level of postsynaptic firing that is
θ LTD θ LTP required in order for afferent stimulation to result in long-
0 term depression (LTD) or long-term potentiation (LTP),
respectively (see Box 2). The effects of prior glutamate
receptor activation (priming) on subsequent LTP and LTD
Group 1 mGluR – Primed are shown in blue and red. NMDA (N-methyl-d-aspartate)
Control receptor (NMDAR) activation (red line) lowers the threshold
NMDAR – Primed for LTD (θLTD) while raising the threshold for LTP (θLTP), as
– LTD shown by the grey arrows. By contrast, group 1
Postsynaptic response metabotropic glutamate receptor (mGluR) activation (blue
line) lowers θLTP , as shown by the black arrow. b | Two
mechanisms that have been suggested to mediate the
b metaplastic effects of metabotropic receptor activation on
LTP induction. In the first, mGluR activation inhibits the
Primed state Glutamate Dopamine Primed state
(induction) (induction) Ca2+-activated K+ channel that mediates the slow after­
hyperpolarization. This mechanism is regulated by the Tyr
Ca2+ K+ phosphorylation state of an unknown regulatory protein
AMPAR AMPAR NMDAR
mGluR1,5 D1,5 (phosphoprotein; Pr). In the second, adenylyl cyclase (AC)
and protein kinase A (PKA) are activated by either
Gq Gs
P PSD stimulation of phospholipase C (PLC) by mGluR and
PLC AC
Pr subsequent release of Ca2+ from intracellular stores or, more
directly, by dopamine D1 or D5 receptor activation of the Gs
cAMP signalling pathway. Activation of PKA causes it to
PTK PTP phosphorylate Ser845 of GluR1, a step which is necessary
IP3 ? PKA for GluR1-containing AMPA (α-amino-3-hydroxy-5-methyl-
4-isoxazole propionic acid) receptors (AMPARs) to be
Pr AMPAR GluR1,2 mRNA
P inserted into the extrasynaptic membrane. The
GluR1
enhancement of AMPAR-subunit mRNA trafficking to
IP3R synaptic sites might also assist this process. c | Mechanisms
Ca2+ mRNA trafficking that have been suggested to mediate the effects of group 1
mGluR activation on the synaptodendritic synthesis of
plasticity-related proteins (PRPs), leading to enhanced LTP
persistence. Evidence suggests that this process is
mediated by the stimulation of PLC and the subsequent
c Glutamate release of Ca2+ from intracellular stores (especially through
ryanodine receptors (RYRs), which might be tethered to
AMPAR NMDAR mGluR sites by Homer1). This Ca2+ release is supplemented
mGluR1,5 SOC
by Ca2+ entry into the cell through store-operated channels
Gq (SOCs) in the plasma membrane. These processes trigger
PLC Homer PSD
the activation of kinases such as extracellular-signal-
Ca2+
Primed state regulated kinase 1 (ERK1), ERK2, protein kinase C (PKC) and
(persistence) α‑calcium/calmodulin-dependent protein kinase II
(αCaMKII), which contribute to the activation of local
IP3 PRPs
αCaMKII protein synthesis machinery. The identity and function of
the PRPs are still being elucidated. cAMP, cyclic AMP;
IP3R RYR ERK1,2 G, G protein; IP3, inositol trisphosphate; IP3R, IP3 receptor;
PKC PSD, postsynaptic density; PTK, phosphotyrosine kinase;
Ca2+ Protein synthesis PTP, phosphotyrosine phosphatase.

magnitude or duration of theNature

increase in the| Neuroscience
Reviews intracellular
free Ca2+ concentration during plasticity induction, lead-
ing to altered enzyme activity3,36,37. More experimental
attention, however, has been given to the effects of prim-
ing on the phosphorylation state of key Ca2+-dependent
kinases, such as α‑calcium/calmodulin-dependent protein
kinase II (αCaMKII)38,39, which has a critical role in initi-
ating LTP by regulating AMPA (α-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid) receptor (AMPAR)
conductance and transport to the membrane 40 .
Mutation of Thr286 of αCaMKII to Ala mimics the
autophosphorylated state of αCaMKII (in which its
activity is Ca2+-independent) and replicates the effects
of NMDAR priming stimulation41. Such autophospho-
rylation might account for the apparent saturation of
LTP following HFS, as LTP is accompanied by a pro-
longed increase in CaMKII autophosphorylation at
Thr286 (Ref. 42). It is not clear, however, whether auto-
phosphorylation of Thr286 can be elicited by priming
stimulation that does not itself cause LTP. The functional
contribution of Thr286 autophosphorylation to meta-
plasticity also remains unclear. It could, for example,

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Calcium/calmodulin-
dependent protein kinase II
(CaMKII). A multi-functional
serine/threonine kinase that is
activated by a Ca2+/calmodulin
complex. Once activated,
CaMKII can autophosphorylate,
leading to autonomous (Ca2+-
independent) activity and
calmodulin trapping. The α
isoform is a major component
of the postsynaptic density
and a key component of the
LTP induction process.
Slow afterhyperpolarization
(slow AHP). A type of
membrane hyperpolarization
that can last for seconds. It is
mediated by the opening of
Ca2+-dependent K+ channels
and is generated in response to
the firing of one or more
postsynaptic Na+ or Ca2+
action potentials.
G-protein-coupled receptors
(GPCRs). A large family of
transmembrane receptors that
couple extracellular signalling
molecules to an intracellular
signalling cascade which they
trigger by activating a G protein.
390 | may 2008 | volume 9 www.nature.com/reviews/neuro
trap calmodulin and prevent it from activating other
enzymes. Indeed, knocking out another binding partner
of calmodulin, RC3 (also known as neurogranin), led to
a decrease in the LTP threshold43.
An alternative aCaMKII autophosphorylation site
that might mediate the inhibition of LTP is Thr305/
Thr306. Priming stimulation of lateral perforant path
synapses in the dentate gyrus prevented subsequent LTP
induction for up to 18 hours, without affecting LTD44.
Mutation of Thr305/Thr306 to prevent aCaMKII auto-
phosphorylation at these sites completely blocked the
metaplasticity. The mutation did not affect metaplastic-
ity in medial perforant path synapses, consistent with
the lack of dependence of LTP on aCaMKII in this input
pathway45.
mGluR-mediated metaplasticity
In contrast to the inhibitory effects of NMDAR priming
on LTP, activation of group 1 metabotropic glutamate
receptors (mGluRs) facilitates both the induction and
the persistence of subsequent LTP in area CA1 (FIG. 1a).
The increased induction is not input specific and seems
to be mediated in part by a long-term downregulation
of the Ca2+-activated K+ current that underlies the slow
afterhyperpolarization (slow AHP)46. This has the effect
of enhancing the level of depolarization that is reached
during HFS (FIG. 1b). The reduction in the slow AHP is
mediated by a non-classical mGluR signalling pathway
that does not involve phospholipase C (PLC), PKC or
the release of Ca2+ from intracellular stores47, but which
is regulated by the degree of Tyr phosphorylation of one
or more unknown regulatory proteins48 (FIG. 1b).
The enhancement of LTP induction by mGluR acti-
vation might also be mediated by increased trafficking
of AMPARs to the extrasynaptic membrane as a result of
PKA-mediated phosphorylation of Ser845 of the GluR1
subunit49,50. This primes the AMPARs for entry into and
capture in the postsynaptic density during subsequent
synaptic activity. This priming process could be ampli-
fied by mGluR-triggered trafficking of the mRNA for
the AMPAR subunits GluR1 and GluR2 into dendrites,
which would expand the pool of receptors that are
available for later insertion51 (FIG. 1b).
mGluR activation might also facilitate NMDAR function
or trafficking, as many G-protein-coupled receptors (GPCRs)
are known to amplify NMDAR currents52,53. Indeed,
activation of muscarinic and corticotropin-releasing
factor receptors, which initiate a signalling cascade that is
similar to that which is initiated by group 1 mGluRs, can
also prime hippocampal LTP54–56. However, preliminary
analysis has suggested that an increase in NMDAR func-
tion is not responsible for the priming of LTP by mGluRs57.
In the prefrontal cortex, GPCR facilitation of subsequent
LTP entails dopamine D1 and D2 receptor activation in
concert with NMDAR activation58. The mechanisms that
are involved in this form of metaplasticity include D1-
receptor-triggered delivery of GluR1-containing AMPARs
to the extrasynaptic membrane59 (FIG. 1b).
Independent of its enhancement of LTP induction,
group 1 mGluR activation can also facilitate the persist-
ence of LTP. For example, HFS of group 1 mGluRs sets
© 2008 Nature Publishing Group
a ‘molecular switch’ that abrogates the need for these
receptors to be activated during subsequent stimulation
in order to generate persistent LTP60. The priming stimu-
lation affects LTP only at primed synapses and lasts for
at least an hour61. The signalling cascade that is involved
in this switch-setting includes the activation of mGluR5,
aCaMKII and PKC62–64.
Similarly, prior pharmacological or HFS priming of
group 1 mGluRs — which by itself does not notably affect
synaptic efficacy — converts a decaying form of LTP into
a longer lasting form55,57,65, an effect that is particularly
prominent in the ventral hippocampus66. The effects of
this priming stimulation are mediated by the activation
of PLC55, the release of Ca2+ from intracellular stores and
the entry of Ca2+ through store-operated Ca2+ channels
in the plasma membrane66,67 (FIG. 1c). Direct priming
activation of the ryanodine receptors that regulate Ca2+
release from intracellular stores also facilitates subsequent
LTP67. Ultimately, these pathways lead to the stimulation
of local protein synthesis at the synapse65, with the newly
synthesized proteins being kept in reserve for enhanc-
ing the persistence of subsequently generated LTP. The
pathway that leads from mGluR stimulation to local
protein synthesis probably entails activation of the pro-
tein kinase mammalian target of rapamycin (mTOR),
which facilitates the translation of terminal oligo­
pyrimidine mRNAs68, as this pathway is also triggered
during mGluR-dependent LTD68 and during a protein-
synthesis-dependent late phase of LTP69. Although it is
not clear which newly synthesized proteins contribute to
the priming of LTP, candidates include elongation factor
1α70, αCaMKII71, elongation factor 2, ribosomal protein
S6 and poly‑A binding protein 1 (Ref. 69).
Priming stimulation of mGluRs affects the plasticity
of medial perforant path synapses in the dentate gyrus,
but the effects are opposite to those described above for
CA1. In the dentate gyrus, prior activation of group 1
or group 2 mGluRs by HFS inhibits subsequent LTP by
activating PKC and p38 MAPK mechanisms31. Under
these conditions, the mGluRs might merely be ampli-
fying the function of NMDARs, which also contribute
to the inhibition of LTP31. Priming HFS also inhibits
mGluR-dependent LTD at these synapses, again through
group-1-mGluR- and PKC-dependent mechanisms, but
independently of NMDARs72.
Heterosynaptic metaplasticity
The metaplasticity examples described above are largely
homosynaptic in nature; that is, the synapses that are
activated during the priming stimulation are also those
that show altered plasticity. However, activity at one set
of synapses can also affect subsequent plasticity at neigh-
bouring synapses. Such heterosynaptic metaplasticity
was predicted by the Bienenstock, Cooper and Munro
computational model of synaptic plasticity73 (BOX 2),
in which cell-wide modifications in the threshold for
LTP induction are driven by the history of postsynaptic
cell firing.
Studies in the hippocampus have begun to reveal
a complex variety of heterosynaptic interactions that
govern LTP induction and persistence. In CA1 in vitro,
 REVIEWS

Box 2 | The Bienenstock, Cooper and Munro model

The Bienenstock, Cooper and Munro (BCM) computational + LTP
Visual deprivation
model of synaptic plasticity was developed to account for
experience-dependent plasticity in the kitten visual

φ (Change in synaptic strength)

cortex73. Subsequently it has been adapted to account for
experience-dependent plasticity in the adult rat barrel Control
cortex and long-term potentiation (LTP) and metaplasticity
in the adult rat dentate gyrus186,187. 0
The model has two principal features. First, it describes θM
the extent of LTP or long-term differentiation (LTD) as a
function (φ) of the degree of postsynaptic cell firing during
afferent activation (see figure). If afferents are active
during times of low postsynaptic activity, those inputs are
depressed. Conversely, if afferents are active during high – LTD
postsynaptic activity, those inputs are potentiated. To Postsynaptic response
preserve stability in the network and prevent runaway
potentiation or depression, the model incorporates a Nature Reviews | Neuroscience
feature that varies the crossover point between LTD and LTP on the φ function, termed the modification threshold (θM), with
the time-averaged level of postsynaptic firing. Thus, if firing levels are maintained at a high level, the modification threshold
shifts to the right, making LTP harder to obtain and LTD easier to obtain. More recent models have combined BCM
principles with experimentally observed features of spike-timing-dependent plasticity, whereby the precise timing of
action-potential firing relative to the synaptic activation determines the direction and degree of synaptic modification186,188.
Although cell firing is the key computational unit of the BCM model, it has been suggested that the physiological metric
used for computing weight changes could be the level of intracellular free Ca2+, as Ca2+ is a key trigger for both LTP and
LTD induction36,189. Subsequently, wholly Ca2+-based models have been generated by Cooper and colleagues, with
particular emphasis on the role that NMDARs have in generating the relevant Ca2+ signals190,191. The resulting Ca2+-
dependent plasticity model, like the BCM model, accounts for many aspects of LTP and LTD induction. Importantly, it also
features homeostatic metaplasticity, which is generated by slow, activity-dependent changes in the regulation of
intracellular Ca2+ levels193.

Depotentiation
A reversal of LTP that brings
synaptic efficacy to a baseline
level. There is growing evidence
that this process involves
mechanisms that are different
to those that mediate LTD.
Antidromic stimulation
The activation of neuronal cell
bodies and dendrites by back-
propagating action potentials
triggered by electrical
stimulation of the cells’ axons.
Plasticity-related proteins
(PRPs). Proteins that are
synthesized in response to
synaptic activation or
postsynaptic activity and that
are necessary for establishing
the persistent forms of LTP and
LTD.
strong priming stimulation of one input pathway facili-
tated the induction of LTD (and depotentiation) and
inhibited the induction of LTP in a neighbouring set of
synapses74,75. This modulation lasted 90–150 minutes
and was not blocked by administration of the NMDAR
antagonist 2-amino-5-phosphonovaleric acid (APV)
during the priming stimulation74. A similar effect, which
was also observed in CA1, required extensive stimula-
tion of the priming pathway and extensive activation of
NMDARs and voltage-dependent Ca2+ channels76. The
molecular mechanisms that mediate such heterosynaptic
inhibitory actions have not yet been investigated.
In the dentate gyrus in vivo, the induction of LTP in
medial perforant path synapses inhibited subsequent
LTP in nearby lateral perforant path synapses, an effect
that lasted for more than 2 days77. In accord with pre-
dictions of the BCM model, simply applying antidromic
stimulation to the postsynaptic granule cells in the pres-
ence of an NMDAR antagonist was sufficient to block
LTP. These results suggest that a cell-wide homeostatic
process adjusts plasticity thresholds to keep the overall
level of synaptic drive to a neuron within a range that
permits plasticity to be expressed.
Synaptic tagging and capture. Despite the appar-
ent theoretical advantages of restraining the overall
amount of LTP that a cell exhibits, there are nonetheless
mechanisms that mediate cooperative and metaplas-
tic upregulation of the persistence of LTP and LTD.
Normally a weak HFS cannot generate the protein-
synthesis-dependent late phases of LTP. However, if a
strong HFS that induces protein-synthesis-dependent
LTP in one input pathway precedes a weak HFS to a
second, independent pathway, this enables the second
pathway to establish a late phase of LTP78 (FIG. 2). This
process is referred to as synaptic tagging79; molecules
in the synapses of the second pathway are said to be
tagged by the weak stimulation in a way that permits
them to capture the proteins that have been synthesized
in response to stronger stimulation elsewhere.
Synaptic tagging is also effective when the regulating
event (the strong HFS) follows the test event (the weak
HFS), in which case the temporal ordering of events
does not fit a metaplasticity paradigm. Nevertheless, this
shows that synaptic tags can be maintained for several
hours post-HFS78, although in vivo they might last for
less than 30 minutes80. The tag can be deleted by LFS
shortly after it is set81, or can be prevented from being
set by prior LFS82 (FIG. 2). The latter protocol affects LTP
maintenance both homosynaptically and heterosyn-
aptically and depends on the activation of the protein
phosphatases 1A and 2A, which reduces the ability of
PKA to participate in tag-setting83,84. Important issues
that remain to be resolved are the identities of the newly
synthesized plasticity-related proteins (PRPs), how these
proteins are captured by the tagged synaptic proteins
and how they promote LTP persistence. Recently a con-
stitutively active PKC isoform, protein kinase Mζ, was
identified as a key PRP. Inhibiting this kinase completely
reversed LTP that was made persistent by the tag-and-
capture process85. Synaptic tagging and capture also
occur for the late phase of LTD86. Remarkably, it seems
not to matter whether late-phase LTD or late-phase LTP
are induced in the first pathway, as either protocol can

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REVIEWS
Back-propagating action
potentials
Action potentials that are
initiated at the soma or the
axon hillock and that
propagate back into the
dendrites, where they shape
the integration of synaptic
activity and influence the
induction of synaptic plasticity.
392 | may 2008 | volume 9 www.nature.com/reviews/neuro
NMDAR 3 if it is given after the weak HFS of the perforant path
Ca2+
1 K+
± −
ECs
CB1R
− heterosynaptic metaplasticity might arise from changes
GABA
2 PRPs
4
+ properties or levels of voltage-dependent Na+, Ca2+,
Pr T
Pr T − 5
PRPs
Pr T
+ Pr T
Figure 2 | Proposed mechanisms of heterosynaptic
metaplasticity. Priming activity at excitatory synapse 1
Nature Reviews | Neuroscience
has the potential to cause lasting inhibition or facilitation
of the Ca -activated K channel mediating the slow after-
2+ +
hyperpolarization (top); to inhibit setting of the synaptic
‘tag’ by a subsequent high-frequency stimulus (synapse 2);
to inhibit NMDA (N-methyl-d-aspartate) receptor
(NMDAR) function (synapse 3); to trigger the production
and release of endocannabinoids (ECs), which cause a
presynaptic inhibition of GABA (γ-aminobutyric acid)
release at inhibitory terminals (synapse 4); and to activate
the synthesis of plasticity-related proteins (PRPs), which
are captured by the synaptic tags that are set by a
subsequent HFS at neighbouring synapses, facilitating the
persistence of the otherwise-decaying long-term
potentiation produced there (synapse 5). CB1R,
cannabinoid receptor 1; Pr, protein; T, tag.
support the development of the late phase of subsequent
LTP or LTD in the second pathway87.
The effects of synaptic tagging are confined to local
dendritic compartments. Thus, protein synthesis that is
stimulated in basal dendrites does not promote LTP or
LTD persistence in the apical dendrites of CA1 pyrami-
dal cells84, presumably because the proteins are generated
synaptodendritically and not somatically88 unless very
strong stimuli are used89,90. This dendritic compart-
mentalization has been proposed to offer computa-
tional advantages for memory formation88. Conversely,
somatically synthesized proteins can protect LTP from
depotentiation in a cell-wide fashion91.
Heterosynaptic metaplasticity that promotes LTP
has also been observed in the dentate gyrus of whole
animals. Stimulation of extrinsic inputs, such as those
that originate from the basolateral amygdala (BLA),
up to 15 minutes before HFS of the perforant path can
facilitate the induction and persistence of LTP80,92, as well
as the induction of LTD93. The facilitated persistence of
LTP is protein-synthesis-dependent and is mediated
by the activation of cholinergic systems in the medial
septum and β‑adrenergic systems arising from the locus
coeruleus80,94,95. The facilitation is itself regulated by the
history of prior BLA stimulation93. As for tagging and
© 2008 Nature Publishing Group
capture, BLA stimulation can reinforce late-phase LTP
or if it is given beforehand80, indicating that PRPs can be
captured at any time as long as the key synaptic molecules
remain tagged.
Metaplasticity arising from changes in cell excitability.
As both LTP and LTD are depolarization-dependent,
in the membrane properties or excitability of the post-
synaptic neuron. Activity-dependent alterations in the
Cl– and K+ channels have been reported (for recent
reviews, see REFS 96–98), and the resultant modification
of cell excitability has been termed intrinsic plasticity96.
Although intrinsic plasticity is likely to be an important
memory mechanism in its own right99, it is also strongly
predicted to be a metaplasticity mechanism that regu-
lates LTP and LTD, given the effects that ion channels
have on transmitter release, postsynaptic depolariza-
tion, the delivery of back-propagating action potentials to
the dendrites and the triggering of protein synthesis and
gene expression.
Although demonstrations of the metaplastic effects
of intrinsic plasticity are rare, progress is being made
towards establishing these effects’ existence. Ca2+-
dependent K+ channels in the postsynaptic membrane
that underlie post-spike AHPs are good candidates
for study because they regulate the threshold for LTP
induction in many neurons100 (FIG. 2). Pharmacological
activation of β‑adrenergic receptors or group 1 mGluRs
can elicit long-lasting reductions in these AHPs, lower-
ing the threshold for LTP induction46. It has been dif-
ficult, however, to demonstrate long-term reductions
in channel function following synaptic stimulation,
although HFS of afferents led to an NMDAR-dependent
and cyclic-AMP/PKA-mediated suppression of the slow
AHP in hippocampal pyramidal cells101. This suppres-
sion lasted for a few minutes and was associated with
facilitation of LTP induction. By contrast, HFS in one
study was found to cause a long-term amplification of the
slow AHP that was associated with the inhibition of
subsequent LTP both homo- and heterosynaptically102.
Other channels that should attract attention include
the A‑type K + channel and the hyperpolarization-
activated cation channel that mediates the non-selective
cation current, Ih, as both regulate LTP and LTD and
both show long-term reductions in function following
synaptic stimulation103,104.
There is now widespread appreciation that the excita-
tory inputs onto GABAergic interneurons can undergo
multiple forms of LTP and LTD, generating changes in
inhibition onto principal cells105–107. Although it is debat-
able whether plasticity of GABAergic signalling per se
is a type of metaplasticity, when postsynaptic excitation
leads to a direct retrograde regulation of neighbouring
GABAergic afferent terminals then its designation as
a metaplasticity mechanism becomes more clear-cut.
Indeed, both evoked and spontaneous presynaptic
release of GABA are transiently inhibited by postsyn-
aptic depolarization or cell firing, in a process termed

Active zone
A portion of the presynaptic
membrane that faces the
postsynaptic density across
the synaptic cleft. It is the site
of synaptic vesicle clustering
and docking and resultant
neurotransmitter release.
Critical period
A finite but modifiable
developmental time window
during which experience
provides information that is
essential for normal
development and permanently
alters brain structure and
performance.
nature reviews | neuroscience volume 9 | may 2008 | 393
depolarization-induced suppression of inhibition
(DSI)108 (FIG. 2). Such plasticity is likely to powerfully
affect the synchrony of cell firing and information
processing in neuronal networks. Moreover, it should
affect the plasticity of excitatory synapses on the princi-
pal neurons, as GABAergic inhibition profoundly affects
plasticity thresholds109,110.
Both DSI and its longer-term counterpart, inhibi-
tory LTD (iLTD) of GABA release (which persists for
more than an hour), are mediated by the activation of
presynaptic cannabinoid 1 (CB1) receptors on the GABA
terminals. These receptors are activated by endogenous
endocannabinoids that serve as retrograde signals follow-
ing postsynaptic group-1 mGluR activation and mem-
brane depolarization111–114 (FIG. 2). During the minute or
so that DSI persists, LTP induction at excitatory inputs
is facilitated115. Similarly, priming-stimulation-induced
iLTD facilitates LTP that is induced at least 60–90 min-
utes later116,117. This latter form of metaplasticity entails
mechanisms that are distinct from those that are at work
in DSI, including CB1-receptor-mediated activation of
presynaptic cAMP/PKA signalling and presumed phos-
phorylation of the active zone protein Rab3-interacting
molecule 1α (Rim1α)116,118. Intriguingly, focal-stimulation
experiments revealed that the spatial spread of iLTD,
and thus the facilitation of LTP, extended 10–40 µm
from the excitatory synapses that were stimulated dur-
ing priming117. This mechanism seems to be well-suited
for promoting bands of localized LTP on the dendrites
of postsynaptic neurons88,119. It could also be an impor-
tant mediator of the mGluR-mediated priming of LTP
described above, although other mechanisms must also
contribute because mGluR priming is observable in the
presence of the GABAA antagonist picrotoxin57.
Behavioural relevance of metaplasticity
Metaplasticity induced by environmental stimuli.
Environmental stimuli, such as enriched environments
or stressful events, can powerfully affect synaptic plas-
ticity. Such regulation could in principle be considered
a form of metaplasticity. However, it is often difficult
to distinguish modulation of plasticity, generated by
the presence of released hormones, catecholamines or
neurotrophic factors, from metaplasticity. One approach
is to use ex vivo experimental preparations, in which
tissue is removed from environmentally stimulated
animals and studied in vitro. This approach has shown
that enriched-environment exposure or exercise can
facilitate LTP induction and persistence120,121, although
others have reported an apparent inhibition of LTP that
was due to occlusion by environmentally induced LTP122.
Intensely stressful stimuli, such as restraint or tail-shock,
reliably inhibit hippocampal LTP and facilitate LTD123.
These effects can be observed for up to 24 hours after
the stressful experience124 and can be blocked by giving
systemic NMDAR antagonists at the time of the stressful
experience123. Remarkably, the same stressor can both
inhibit LTP through glucocorticoid receptor activation
in the dorsal hippocampus and facilitate LTP through
mineralocorticoid receptor activation in the ventral
hippo­campus125.
© 2008 Nature Publishing Group
REVIEWS
Is the inhibition of LTP by stress a metaplastic effect
or simply an occlusion of further LTP by stress-induced
LTP126–129? Evidence that it might be the latter is provided
by the fact that strong fear conditioning leads to a poten-
tiation of responses that lasts for up to 7 days in CA1
(Ref. 130) and for at least 24 hours in the cerebellum131.
However, as the inhibition of LTP in CA1 lasted for only
1 day132 whereas the response potentiation persisted for 7
days, it seems that response potentiation per se is not suf-
ficient to account for the lack of further LTP in the hip-
pocampus. This suggests that a simultaneous induction
of NMDAR-mediated LTP and metaplasticity prevents
further LTP.
Developmental metaplasticity in the visual cortex. Dark
rearing can reduce the thresholds for LTP and LTD in
visual cortical neurons 133,134. Exposing dark-reared
animals to light for 2 days completely reverses these
effects133, which might be mediated at least in part by
an experience-dependent switch in NMDAR subunit
composition. Early in life, NR2B is the predominant
NR2 subunit of NMDARs in the visual cortex135. During
normal developmental maturation through the critical
period, NR2A subunits become more prominent135. In
dark-reared animals this maturational change is reduced,
but 2 hours of light exposure is sufficient to markedly
increase the proportion of NR2A-containing receptors136.
An even faster activity-dependent switch in NMDAR
subunit composition following tetanic stimulation has
been reported in neonatal hippocampal neurons137.
Because NR2A-containing receptors produce cur-
rents that are shorter than those that are produced by
NR2B-containing receptors, and because they should
thus be associated with reduced synaptic Ca 2+ accu-
mulation138, the subunit composition of NMDARs was
predicted to account for the effects of dark rearing and
subsequent light exposure on plasticity thresholds.
Indeed, pharmacological agents that mimicked the
effects of light exposure on dark-reared rats by short-
ening NMDAR currents also reproduced the elevation
in LTD threshold134, whereas NR2A-knockout mice lost
the capacity for visual experience to metaplastically
regulate their plasticity thresholds139. The prominence
of the subunit-switch hypothesis, however, does not
rule out other development- and experience-dependent
changes, such as altered levels of GABAergic inhibition,
brain-derived neurotrophic factor or other modulatory
agents, contributing to the metaplastic effects.
Learning-associated metaplasticity. A key issue is
whether metaplasticity is important for learning. Does
learning cause metaplasticity that influences either the
current period of acquisition or the learning of new
information in the future? Certainly stressful stimuli or
enriched environments can affect synaptic plasticity in
addition to learning and memory, but the link between
learning and metaplasticity remains uncertain. There is
growing evidence, however, that learning-induced long-
term alterations in AHPs might directly affect new learn-
ing. It is now well established that reflex conditioning in
invertebrates and mammals produces intrinsic plasticity
REVIEWS

Odour-discrimination training Eye-blink conditioning prolonged increase in PKC, extracellular-signal-regulated

kinase 1 (ERK1) and ERK2 activity146. Curiously, at
W N
P approximately the time that olfactory-discrimination
learning reduces the slow AHP, there is a shift in plastic-
ity thresholds in the olfactory cortex towards enhanced
LTD and reduced LTP148,149, as well as an increase in the
NR2A/NR2B ratio for piriform NMDARs149.
An increased slow AHP, which can, for example, be
Piriform CA1 induced by aging and by increased levels of corticoster-
pyramidal cell pyramidal cell
Pre Post one, impairs learning and memory150. Similarly, it has
been proposed that a reduction of the slow AHP might be
critical for the learning process: it might metaplastically
lower the threshold for LTP150. Moreover, the changed
neuronal state that is represented by the reduced slow
AHP might provide an improved environment for new
learning. These concepts were lent support when olfac-
tory-discrimination training was observed to reduce
the slow AHP in rat CA1 pyramidal neurons of trained
Odour-discrimination- Spatial learning
rule learning but not pseudo-trained animals151. The slow AHP
90 ** reduction occurred before there was any behavioural
Controls **
80
Trained **
evidence that the discrimination rule had been learned,
Success (%)

70 and was reversed once the learning rule was acquired.

60 Importantly, the ability to learn a different task for which
50 CA1 cells are important — spatial navigation in a water
40 maze — was enhanced during the time period that the
30
1 2 3 4 5 6 7 8
slow AHP was reduced151 (FIG. 3).
Training days Another potential metaplasticity mechanism that
might enhance the neuronal environment for learning
Figure 3 | Proposals for metaplasticity thatNature
is induced during
Reviews learning. Training can
| Neuroscience can be inferred from the dependence of transcriptional
induce a reduction of the slow afterhyperpolarization (slow AHP) and a corresponding processes on the state of histone acetylation and DNA
increase in cell excitability. Odour-discrimination training can cause these effects to
methylation. Animals that have been trained on memory
occur in both piriform and CA1 pyramidal cells and lead to a facilitation of odour-
discrimination-rule learning as well as spatial-memory acquisition in the water maze.
tasks show increased histone acetylation in relevant
Eye-blink conditioning and spatial training in the water maze can also elicit these brain regions, and pharmacological inhibition of his-
physiological changes in CA1 pyramidal cells. Such changes might be important for the tone deacetylase promotes the formation of long-term
early phases of learning in these tasks. However, other mechanisms are not excluded. The memory and a late phase of LTP152. Conversely, inhibi-
top left section of the figure depicts the odour-discrimination apparatus, including the tors of DNA methylation block memory consolidation and
odour ports P (the site of the rewarded stimulus) and N (the site of the non-rewarded inhibit the late phase of LTP153,154. These data suggest that
stimulus) and the water-reward port (W). The bottom left section shows the acquisition of the proteins that are synthesized as a result of learning-
a response to the positive odour in the trained animals and no learning in the control activated transcription might promote subsequent long-
pseudo-trained animals. The top waveforms illustrate the slow AHP pre-training (Pre) and term memory formation in a new task, as long as there
how it might look after being reduced by training (Post). The bottom waveforms illustrate
is overlap of the neurons participating in the learning
the corresponding increase in action-potential firing to a depolarizing-current pulse. The
sections illustrating odour-discrimination training are modified, with permission, from
of the two tasks and as long as the proteins produced
REF.151  (2006) Oxford University Press. The piriform pyramidal cell was kindly provided during the first task can be captured by molecules
by John Bekkers and Noromitsu Suzuki (Australian National University). The tagged during learning of the second task.
reconstructed CA1 pyramidal cell was kindly provided by Clarke Raymond (Australian In a different model, single-whisker stimulation gen-
National University). erates NMDAR-dependent LTP of connections between
layer 4 and layer 2/3 neurons in the barrel cortex155.
Eventually potentiation stabilizes owing to NMDAR-
of cell excitability140–142. In rabbit eye-blink conditioning, dependent inhibition of LTP. However, additional
Eye-blink conditioning
A classical conditioning
learning-induced reductions in the slow AHP and whisker stimulation can increase responses further
paradigm that is commonly increases in cell firing in response to a depolarizing cur- through a metaplastic recruitment of mGluR-dependent
used for the study of learning. rent pulse lasted for up to 5 days in CA1 pyramidal cells143 mechanisms, if the inhibitory effect of NMDARs is
In it, an eye-blink, or the (FIG. 3). These changes were not observed in animals that pharmacologically blocked155. These findings indicate
retraction of the nictitating
were given the same conditioned and unconditioned that NMDAR inhibition and mGluR facilitation of LTP
membrane over the eye, is
reflexively conditioned by stimuli but in a random order. Similar effects have been are in a dynamic balance and are regulated by sensory
pairing a conditioned neutral reported in rat CA1 pyramidal cells following spatial experience.
stimulus such as a tone with water maze training144 and in piriform cortical neurons
an aversive stimulus such as an after operant conditioning and olfactory-discrimination Clinical relevance
air-puff to the eye. After
sufficient pairings the
training145,146, where a persistent decrease in the apamin- Learning and memory mechanisms lie at the heart of all
conditioned stimulus can elicit sensitive medium AHP was also observed147 (FIG. 3). The cognitive functions, and synaptic plasticity is vital for
the eye-blink response by itself. persistent decrease in the slow AHP is mediated by a normal cognition and behaviour. Not surprisingly, many

394 | may 2008 | volume 9 www.nature.com/reviews/neuro

© 2008 Nature Publishing Group

Memory consolidation
A protein-synthesis-dependent
process of memory
stabilization occuring over
hours in animals and for up to
years in humans that renders
the memory resistant to
change.
Amblyopia
Poor vision, usually occurring
in one eye, that is associated
with a prolonged period of
indistinct visual stimulation or
visual system dysfunction
during development.
Ischaemic preconditioning
(IPC). A phenomenon observed
both clinically and
experimentally whereby a mild
ischaemic event ‘primes’ a
tissue by activating
endogenous cellular protective
mechanisms that amelioriate
the neurotoxic outcome of a
later, more severe ischaemic
event.
nature reviews | neuroscience volume 9 | may 2008 | 395
neurological disorders entail learning and memory defi-
cits, and animal models of Alzheimer’s disease156, head
injury157,158, stroke159, epilepsy160, Down syndrome161,
Fragile X-linked mental retardation syndrome 162,
Parkinson’s disease163 and Huntington’s disease164 all
show evidence of dsyregulated synaptic plasticity.
Furthermore, abnormal conditions such as prolonged
inhibition of synaptic input can lead to alterations in
synaptic receptor complement and ion-channel expres-
sion165. Insofar as these latter changes return neurons
to a pre-existing level of activity, they can be viewed as
being homeostatic in nature. However, as some changes
include increased expression of Ca2+-conducting gluta-
mate receptors/channels, such as NMDARs and GluR2-
lacking AMPARs, they could serve a metaplasticity
function as well19,166,167. Hyperactivity during epilepsy
also upregulates GluR2-lacking AMPARs, which might
promote pathological levels of plasticity168. Therefore, it
is important to understand regulatory mechanisms such
as metaplasticity both to gain insight into disease mecha-
nisms and to provide targets for promoting functional
recovery and repair.
An excellent example of how metaplasticity might
be harnessed for clinical purposes arose from studies
of visual cortex plasticity, which have challenged the
conventional wisdom that the adult visual cortex cannot
exhibit the experience-dependent plasticity that is seen
in juveniles. In fact, a nearly complete capacity for ocular
dominance shifts is observed in the visual cortex fol-
lowing monocular visual deprivation (MD) when adult
animals are given 7 days of dark exposure shortly before
the MD169. Furthermore, prior experience with transient
MD, either during development or as an adult, sensitizes
the adult cortex to future bouts of MD, leading to more
rapid and persistent changes170. Importantly, it has been
reported that the loss of visual acuity (amblyopia) that is
associated with chronic MD can be significantly reversed
if the animals are given either 3–10 days of dark expo-
sure before the return of vision to the occluded eye171 or
2–3 weeks of enriched-environment exposure172. These
effects presumably occur by reducing plasticity thresh-
olds through a return to the juvenile (NR2B-containing)
form of NMDARs and decreasing the inhibition–
excitation ratio169,172. These exciting experiments sug-
gest that metaplastic alteration of the threshold of cor-
tical synapses for synaptic change might be a possible
therapeutic approach to adult amblyopia.
Another consideration is that metaplasticity, by
homeostatically preventing the saturation of synaptic
potentiation, might guard against excitotoxicity or
epilepsy. Indeed, synaptic or pharmacological stimula-
tion of glutamate receptors can inhibit the subsequent
induction of epileptic seizures173,174. Furthermore, some
metaplasticity control mechanisms might be part of a
larger repertoire of endogenous cellular mechanisms that
protect against excitotoxicity and death — for example,
those that are involved in ischaemic preconditioning (IPC)
(for reviews, see REFS 175–177). The induction of IPC
bears some similarity to a metaplasticity protocol and
might entail overlapping signalling molecules and cellu-
lar processes, such as NMDARs, mGluRs, adenosine and
© 2008 Nature Publishing Group
REVIEWS
protein synthesis. Also, both phenomena exhibit short-
term (minutes–hours) and long-term (days) modes of
operation. Accordingly, understanding the mechanisms
that mediate metaplasticity might help us to generate
new hypotheses regarding the molecular mechanisms
of IPC and might help us to identify new therapeutic
targets for experimental testing.
Implications for network function
Given how robust synaptic plasticity can be, there is a
clear need for homeostatic controls, to prevent LTP from
occurring too readily in response to weak stimuli or to
too great an extent after strong stimuli, with possible
resultant excitotoxicity. Conversely, metaplasticity can
prevent a network from becoming incapacitated by too
much LTD or by loss of afferent input178. Such controls
have been predicted on theoretical grounds in network
models and have been shown empirically to operate
in practice.
An important implication of metaplasticity is that
metaplasticity mechanisms can be operative even during
plasticity induction. Thus, changes to plasticity thresh-
olds early during an induction protocol might facilitate
plasticity induction by later stimuli16. This seems to hap-
pen during learning as well150,151. Thus, metaplasticity
mechanisms might begin to function relatively quickly
after their engagement, in order to put synapses and
networks into a learning-ready state. The possible co-
engagement of metaplasticity and plasticity mechanisms
renders it difficult to ascribe particular molecular changes
induced by conditioning stimulation to one mechanism
or the other. Protein synthesis, for example, can promote
plasticity persistence (or memory consolidation) but can
also raise the threshold for reversing the plasticity (the
memory) as a metaplasticity mechanism. Subsequent
stimulus patterns or, in the case of memory, environ-
mental cues might then first have to lower the plasticity
thresholds at these synapses before additional
plasticity (learning) can occur. Thus, it needs to be clari-
fied which proteins serve plasticity versus metaplasticity
functions or, alternatively, whether the two outcomes
derive from the activation of common effectors.
A third general contribution that metaplasticity might
make is to the prolongation of memory retention. Models
of dynamically learning neural networks have shown that
incorporating multiple metaplastic states at the learning
nodes of the model helps to keep previously learned
information from being overwritten by new learning179,180.
It is interesting to note, therefore, that in hippocampal
organotypic cultures up to five discrete synaptic states
have been described, with the number being dependent
on both the degree of synaptic efficacy evident at the syn-
apse and the history of prior activity that generated that
level of efficacy181. Furthermore, these postsynaptic states
could be multiplicatively amplified by state-dependent
modulation of plasticity at presynaptic release sites182.
Concluding remarks
Like synaptic plasticity — and, indeed, memory — the
term metaplasticity refers to a variety of processes
that layer over each other. Synapse-specific regulation
REVIEWS

provides local control, whereas wider heterosynaptic
and network changes provide more global regulation.
Together, these metaplasticity processes represent a
major form of adaptation that helps to keep synaptic
efficacy within a dynamic range and larger neural net-
works in the appropriate state for learning. However, the
metaplasticity field is still young, and more extensive
studies are required of its molecular mechanisms, their
effects on network function and their contributions to
learning and memory. Harnessing these regulatory
mechanisms might also prove to have important clini-
cal usefulness, particularly as the more tempting direct
manipulations of plasticity processes are likely to be
fraught with severe side-effects. However, with the
multitude of possible mechanisms for study and
the excitement which that generates comes the caution
that not all plasticity regulation is metaplasticity, and it
is important to retain rigor in the design and interpre-
tation of the experiments that address this fascinating
and complex topic.

1. Martin, S. J., Grimwood, P. D. & Morris, R. G. M.
Synaptic plasticity and memory: an evaluation of the
hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).
2. Neves, G., Cooke, S. F. & Bliss, T. V. P. Synaptic
plasticity, memory and the hippocampus: a neural
network approach to causality. Nature Rev. Neurosci.
9, 65–75 (2008).
3. Abraham, W. C. & Bear, M. F. Metaplasticity: the
plasticity of synaptic plasticity. Trends Neurosci. 19,
126–130 (1996).
This paper provided the first formal description
and review of metaplasticity phenomena.
4. Abraham, W. C. & Tate, W. P. Metaplasticity: a new
vista across the field of synaptic plasticity. Prog.
Neurobiol. 52, 303–323 (1997).
5. Huang, Y. Y., Colino, A., Selig, D. K. & Malenka, R. C.
The influence of prior synaptic activity on the induction
of long-term potentiation. Science 255, 730–733
(1992).
This key paper provided the first clear
demonstration that prior activation of NMDARs
can inhibit the induction of subsequent LTP.
6. Coan, E. J., Irving, A. J. & Collingridge, G. L. Low-
frequency activation of the NMDA receptor system
can prevent the induction of LTP. Neurosci. Lett. 105,
205–210 (1989).
7. Youssef, F. F., Addae, J. I. & Stone, T. W. NMDA-induced
preconditioning attenuates synaptic plasticity in the rat
hippocampus. Brain Res. 1073, 183–189 (2006).
8. Fujii, S. et al. The long-term suppressive effect of prior
activation of synaptic inputs by low-frequency
stimulation on induction of long-term potentiation in
CA1 neurons of guinea pig hippocampal slices. Exp.
Brain Res. 111, 305–312 (1996).
9. Woo, N. H. & Nguyen, P. V. “Silent” metaplasticity of
the late phase of long-term potentiation requires
protein phosphatases. Learn. Mem. 9, 202–213 (2002).
10. Fujii, S. et al. Endogenous adenosine regulates the
effects of low-frequency stimulation on the induction of
long-term potentiation in CA1 neurons of guinea pig
hippocampal slices. Neurosci. Lett. 279, 121–124
(2000).
11. Izumi, Y., Tokuda, K. & Zorumski, C. F. Long-term
potentiation inhibition by low-level N‑methyl‑d-
aspartate receptor activation involves calcineurin,
nitric oxide, and p38 mitogen-activated protein
kinase. Hippocampus 18, 258–265 (2008).
12. O’Connor, D. H., Wittenberg, G. M. & Wang, S. S. H.
Dissection of bidirectional synaptic plasticity into
saturable unidirectional processes. J. Neurophysiol.
94, 1565–1573 (2005).
13. Abraham, W. C. & Huggett, A. Induction and reversal
of long-term potentiation by repeated high-frequency
stimulation in rat hippocampal slices. Hippocampus 7,
137–145 (1997).
14. Christie, B. R. & Abraham, W. C. Priming of associative
long-term depression by θ frequency synaptic activity.
Neuron 8, 79–84 (1992).
15. Wang, Y., Wu, J., Rowan, M. J. & Anwyl, R. Role of
protein kinase C in the induction of homosynaptic
long-term depression by brief low frequency stimulation
in the dentate gyrus of the rat hippocampus in vitro.
J. Physiol. 513, 467–475 (1998).
16. Mockett, B., Coussens, C. & Abraham, W. C. NMDA
receptor-mediated metaplasticity during the induction
of long-term depression by low-frequency stimulation.
Eur. J. Neurosci. 15, 1819–1826 (2002).
This paper provided the first demonstration that
the induction of LTD by LFS involves an initial
NMDAR-induced reduction in the threshold for LTD
by pulses early in the LFS, so that pulses later in
the LFS can induce the LTD.
17. Ngezahayo, A., Schachner, M. & Artola, A. Synaptic
activity modulates the induction of bidirectional
synaptic changes in adult mouse hippocampus.
J. Neurosci. 20, 2451–2458 (2000).
18. Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in
synaptic plasticity and neuropsychiatric disorders.
Nature Rev. Neurosci. 8, 413–426 (2007).
19. Perez-Otano, I. & Ehlers, M. D. Homeostatic plasticity
and NMDA receptor trafficking. Trends Neurosci. 28,
229–238 (2005).
20. Selig, D. K., Hjelmstad, G. O., Herron, C., Nicoll, R. A.
& Malenka, R. C. Independent mechanisms for long-
term depression of AMPA and NMDA responses.
Neuron 15, 417–426 (1995).
21. Morishita, W., Marie, H. & Malenka, R. C. Distinct
triggering and expression mechanisms underlie LTD of
AMPA and NMDA synaptic responses. Nature
Neurosci. 8, 1043–1050 (2005).
22. Sobczyk, A. & Svoboda, K. Activity-dependent
plasticity of the NMDA-receptor fractional Ca2+
current. Neuron 53, 17–24 (2007).
This paper provided a clear demonstration, using
2‑photon release of caged glutamate, that synaptic
activation of NMDARs can lead to down-regulation
of NMDAR function and thus serve as a possible
mechanism of metaplasticity.
23. Kato, K. & Zorumski, C. F. Nitric oxide inhibitors
facilitate the induction of hippocampal long-term
potentiation by modulating NMDA responses.
J. Neurophysiol. 70, 1260–1263 (1993).
24. Murphy, K. P. S. J., Williams, J. H., Bettache, N. & Bliss,
T. V. P. Photolytic release of nitric oxide modulates
NMDA receptor-mediated transmission but does not
induce long-term potentiation at hippocampal synapses.
Neuropharmacology 33, 1375–1385 (1994).
25. Fong, D. K., Rao, A., Crump, F. T. & Craig, A. M. Rapid
synaptic remodeling by protein kinase C: reciprocal
translocation of NMDA receptors and calcium/
calmodulin-dependent kinase II. J. Neurosci. 22,
2153–2164 (2002).
26. Groc, L. et al. Differential activity-dependent regulation
of the lateral mobilities of AMPA and NMDA receptors.
Nature Neurosci. 7, 695–696 (2004).
27. Montgomery, J., Selcher, J., Hanson, J. & Madison, D.
Dynamin-dependent NMDAR endocytosis during LTD
and its dependence on synaptic state. BMC Neurosci.
6, 48 (2005).
28. Stanton, P. K. Transient protein kinase C activation
primes long-term depression and suppresses long-
term potentiation of synaptic transmission in
hippocampus. Proc. Natl Acad. Sci. USA 92,
1724–1728 (1995).
29. Izumi, Y., Clifford, D. B. & Zorumski, C. F. Inhibition of
long-term potentiation by NMDA-mediated nitric
oxide release. Science 257, 1273–1276 (1992).
30. Hsu, K. S., Ho, W. C., Huang, C. C. & Tsai, J. J.
Transient removal of extracellular Mg2+ elicits
persistent suppression of LTP at hippocampal CA1
synapses via PKC activation. J. Neurophysiol. 84,
1279–1288 (2000).
31. Gisabella, B., Rowan, M. J. & Anwyl, R. Mechanisms
underlying the inhibition of long-term potentiation by
preconditioning stimulation in the hippocampus
in vitro. Neuroscience 121, 297–305 (2003).
32. Waxman, E. A. & Lynch, D. R. N‑methyl‑d-aspartate
receptor subtype mediated bidirectional control of
p38 mitogen-activated protein kinase. J. Biol. Chem.
280, 29322–29333 (2005).
33. McNaughton, B. L., Douglas, R. M. & Goddard, G. V.
Synaptic enhancement in fascia dentate: cooperativity
among coactive afferents. Brain Res. 157, 277–293
(1978).
34. Frey, U., Schollmeier, K., Reymann, K. G. &
Seidenbecher, T. Asymptotic hippocampal long-term
potentiation in rats does not preclude additional
potentiation at later phases. Neuroscience 67,
799–807 (1995).
This important paper demonstrated that the
apparent saturation of LTP by repeated HFS can, in
some situations at least, simply reflect a transient
metaplastic inhibition of further LTP. Thus,
additional LTP can be obtained by an HFS given
after a rest period.
35. Moody, T. D., Carlisle, H. J. & O’Dell, T. J. A nitric
oxide-independent and β‑adrenergic receptor-sensitive
form of metaplasticity limits θ-frequency stimulation-
induced LTP in the hippocampal CA1 region. Learn.
Mem. 6, 619–633 (1999).
36. Gold, J. I. & Bear, M. F. A model of dendritic spine
Ca2+ concentration exploring possible bases for a
sliding synaptic modification threshold. Proc. Natl
Acad. Sci. USA 91, 3941–3945 (1994).
37. Alkon, D. L. et al. Learning and memory. FENS Study
Group. Brain Res. Brain Res. Rev. 16, 193–220
(1991).
38. Bear, M. F. Mechanism for a sliding synaptic
modification threshold. Neuron 15, 1–4 (1995).
39. Deisseroth, K., Bito, H., Schulman, H. & Tsien, R. W.
A molecular mechanism for metaplasticity. Curr. Biol.
5, 1334–1338 (1995).
40. Mauceri, D., Cattabeni, F., Di Luca, M. & Gardoni, F.
Calcium/calmodulin-dependent protein kinase II
phosphorylation drives synapse-associated protein 97
into spines. J. Biol. Chem. 279, 23813–23821
(2004).
41. Mayford, M., Wang, J., Kandel, E. R. & O’Dell, T. J.
CaMKII regulates the frequency-response function of
hippocampal synapses for the production of both LTD
and LTP. Cell 81, 891–904 (1995).
42. Fukunaga, K., Stoppini, L., Miyamoto, E. & Muller, D.
Long-term potentiation is associated with an increased
activity of Ca2+/calmodulin-dependent protein kinase II.
J. Biol. Chem. 268, 7863–7867 (1993).
43. Krucker, T. et al. Targeted disruption of RC3 reveals a
calmodulin-based mechanism for regulating
metaplasticity in the hippocampus. J. Neurosci. 22,
5525–5535 (2002).
44. Zhang, L. et al. Hippocampal synaptic metaplasticity
requires inhibitory autophosphorylation of Ca2+/
calmodulin-dependent kinase II. J. Neurosci. 25,
7697–7707 (2005).
This paper provided a key demonstration that
phosphorylation of the Thr305/Thr306 site on
αCaMKII mediates the metaplastic inhibition of LTP
by synaptic activity.
45. Cooke, S. F. et al. Autophosphorylation of αCaMKII is
not a general requirement for NMDA receptor-
dependent LTP in the adult mouse. J. Physiol. 574,
805–818 (2006).
46. Cohen, A. S., Coussens, C. M., Raymond, C. R. &
Abraham, W. C. Long-lasting increase in cellular
excitability associated with the priming of LTP
induction in rat hippocampus. J. Neurophysiol. 82,
3139–3148 (1999).
47. Ireland, D. R. & Abraham, W. C. Group I mGluRs
increase excitability of hippocampal CA1 pyramidal
neurons by a PLC-independent mechanism.
J. Neurophysiol. 88, 107–116 (2002).
48. Ireland, D. R., Guevremont, D., Williams, J. M. &
Abraham, W. C. Metabotropic glutamate receptor-
mediated depression of the slow
afterhyperpolarization is gated by tyrosine
phosphatases in hippocampal CA1 pyramidal neurons.
J. Neurophysiol. 92, 2811–2819 (2004).

396 | may 2008 | volume 9 www.nature.com/reviews/neuro

© 2008 Nature Publishing Group

49. Oh, M. C., Derkach, V. A., Guire, E. S. & Soderling,
T. R. Extrasynaptic membrane trafficking regulated by
GluR1 serine 845 phosphorylation primes AMPA
receptors for long-term potentiation. J. Biol. Chem.
281, 752–758 (2006).
This study provided an important hippocampal
demonstration that trafficking of AMPARs to the
extrasynaptic membrane can prime synapses for
enhanced LTP in response to a subsequent HFS.
50. Gao, C., Sun, X. & Wolf, M. E. Activation of D1
dopamine receptors increases surface expression of
AMPA receptors and facilitates their synaptic
incorporation in cultured hippocampal neurons.
J. Neurochem. 98, 1664–1677 (2006).
51. Grooms, S. Y. et al. Activity bidirectionally regulates
AMPA receptor mRNA abundance in dendrites of
hippocampal neurons. J. Neurosci. 26, 8339–8351
(2006).
52. O’Connor, J. J., Rowan, M. J. & Anwyl, R. Long-lasting
enhancement of NMDA receptor-mediated synaptic
transmission by metabotropic glutamate receptor
activation. Nature 367, 557–559 (1994).
53. MacDonald, J. F., Jackson, M. F. & Beazely, M. A.
G protein-coupled receptors control NMDARs and
metaplasticity in the hippocampus. Biochim. Biophys.
Acta 1768, 941–951 (2007).
54. Christie, B. R., Stellwagen, D. & Abraham, W. C.
Reduction of the threshold for long-term potentiation
by prior theta-frequency synaptic activity.
Hippocampus 5, 52–59 (1995).
55. Cohen, A. S., Raymond, C. R. & Abraham, W. C.
Priming of long-term potentiation induced by
activation of metabotropic glutamate receptors
coupled to phospholipase C. Hippocampus 8,
160–170 (1998).
56. Blank, T., Nijholt, I., Eckart, K. & Spiess, J. Priming of
long-term potentiation in mouse hippocampus by
corticotropin-releasing factor and acute stress:
implications for hippocampus-dependent learning.
J. Neurosci. 22, 3788–3794 (2002).
57. Cohen, A. S. & Abraham, W. C. Facilitation of long-
term potentiation by prior activation of metabotropic
glutamate receptors. J. Neurophysiol. 76, 953–962
(1996).
58. Matsuda, Y., Marzo, A. & Otani, S. The presence of
background dopamine signal converts long-term
synaptic depression to potentiation in rat prefrontal
cortex. J. Neurosci. 26, 4803–4810 (2006).
59. Sun, X., Zhao, Y. & Wolf, M. E. Dopamine receptor
stimulation modulates AMPA receptor synaptic
insertion in prefrontal cortex neurons. J. Neurosci. 25,
7342–7351 (2005).
60. Bortolotto, Z. A., Bashir, Z. I., Davies, C. H. &
Collingridge, G. L. A molecular switch activated by
metabotropic glutamate receptors regulates induction
of long-term potentiation. Nature 368, 740–743
(1994).
This paper provided the first demonstration that
activation of mGluRs can metaplastically promote
subsequent LTP induction, in this case by changing
the state of the synapses so as to render further
activation of mGluRs unnecessary for LTP.
61. Bortolotto, Z. A. et al. Studies on the role of
metabotropic glutamate receptors in long-term
potentiation: some methodological considerations.
J. Neurosci. Methods 59, 19–24 (1995).
62. Bortolotto, Z. A. et al. The regulation of hippocampal
LTP by the molecular switch, a form of metaplasticity,
requires mGlu5 receptors. Neuropharmacology 49,
13–25 (2005).
63. Bortolotto, Z. A. & Collingridge, G. L. Involvement of
calcium/calmodulin-dependent protein kinases in the
setting of a molecular switch involved in hippocampal
LTP. Neuropharmacology 37, 535–544 (1998).
64. Bortolotto, Z. A. & Collingridge, G. L. A role for protein
kinase C in a form of metaplasticity that regulates the
induction of long-term potentiation at CA1 synapses of
the adult rat hippocampus. Eur. J. Neurosci. 12,
4055–4062 (2000).
65. Raymond, C. R., Thompson, V. L., Tate, W. P. &
Abraham, W. C. Metabotropic glutamate receptors
trigger homosynaptic protein synthesis to prolong
long-term potentiation. J. Neurosci. 20, 969–976
(2000).
66. Maggio, N. & Segal, M. Unique regulation of long
term potentiation in the rat ventral hippocampus.
Hippocampus 17, 10–25 (2007).
67. Mellentin, C., Jahnsen, H. & Abraham, W. C. Priming
of long-term potentiation mediated by ryanodine
receptor activation in rat hippocampal slices.
Neuropharmacology 52, 118–125 (2007).
nature reviews | neuroscience volume 9 | may 2008 | 397
68. Klann, E. & Dever, T. E. Biochemical mechanisms for
translational regulation in synaptic plasticity. Nature
Rev. Neurosci. 5, 931–942 (2004).
69. Tsokas, P., Ma, T., Iyengar, R., Landau, E. M. & Blitzer,
R. D. Mitogen-activated protein kinase upregulates
the dendritic translation machinery in long-term
potentiation by controlling the mammalian target of
rapamycin pathway. J. Neurosci. 27, 5885–5894
(2007).
70. Huang, F., Chotiner, J. K. & Steward, O. The mRNA for
elongation factor 1α is localized in dendrites and
translated in response to treatments that induce long-
term depression. J. Neurosci. 25, 7199–7209
(2005).
71. Ouyang, Y., Rosenstein, A., Kreiman, G., Schuman,
E. M. & Kennedy, M. B. Tetanic stimulation leads to
increased accumulation of Ca2+/calmodulin-dependent
protein kinase II via dendritic protein synthesis in
hippocampal neurons. J. Neurosci. 19, 7823–7833
(1999).
72. Rush, A. M., Wu, J. Q., Rowan, M. J. & Anwyl, R.
Group I metabotropic glutamate receptor (mGluR)-
dependent long-term depression mediated via p38
mitogen-activated protein kinase is inhibited by
previous high-frequency stimulation and activation of
mGluRs and protein kinase C in the rat dentate gyrus
in vitro. J. Neurosci. 22, 6121–6128 (2002).
73. Bienenstock, E. L., Cooper, L. N. & Munro, P. W.
Theory for the development of neuron selectivity:
orientation specificity and binocular interaction in
visual cortex. J. Neurosci. 2, 32–48 (1982).
This seminal paper described a model designed to
account for the various features of experience-
dependent plasticity in the visual cortex. Now
known as the BCM model, the work inspired
numerous experimental tests of its essential
principles.
74. Holland, L. L. & Wagner, J. J. Primed facilitation of
homosynaptic long-term depression and
depotentiation in rat hippocampus. J. Neurosci. 18,
887–894 (1998).
75. Wang, H. & Wagner, J. J. Priming-induced shift in
synaptic plasticity in the rat hippocampus.
J. Neurophysiol. 82, 2024–2028 (1999).
76. Roth-Alpermann, C., Morris, R. G. M., Korte, M. &
Bonhoeffer, T. Homeostatic shutdown of long-term
potentiation in the adult hippocampus. Proc. Natl
Acad. Sci. USA 103, 11039–11044 (2006).
77. Abraham, W. C., Mason-Parker, S. E., Bear, M. F.,
Webb, S. & Tate, W. P. Heterosynaptic metaplasticity
in the hippocampus in vivo: a BCM-like modifiable
threshold for LTP. Proc. Natl Acad. Sci. USA 98,
10924–10929 (2001).
78. Frey, U. & Morris, R. G. M. Synaptic tagging and long-
term potentiation. Nature 385, 533–536 (1997).
This paper described the concept of synaptic
tagging for the first time. Experimental evidence
was presented for an interaction between a
strongly activated input pathway and a weakly
activated pathway. This interaction promotes
protein-synthesis-dependent LTP in the weak
pathway.
79. Frey, U. & Morris, R. G. M. Synaptic tagging:
implications for late maintenance of hippocampal
long-term potentiation. Trends Neurosci. 21,
181–188 (1998).
80. Frey, S., Bergado-Rosado, J., Seidenbecher, T., Pape,
H. C. & Frey, J. U. Reinforcement of early long-term
potentiation (early-LTP) in dentate gyrus by
stimulation of the basolateral amygdala:
heterosynaptic induction mechanisms of late-LTP.
J. Neurosci. 21, 3697–3703 (2001).
81. Sajikumar, S. & Frey, J. U. Resetting of ‘synaptic tags’
is time- and activity-dependent in rat hippocampal
Ca1 in vitro. Neuroscience 129, 503–507 (2004).
82. Young, J. Z. & Nguyen, P. V. Homosynaptic and
heterosynaptic inhibition of synaptic tagging and
capture of long-term potentiation by previous
synaptic activity. J. Neurosci. 25, 7221–7231
(2005).
83. Young, J. Z., Isiegas, C., Abel, T. & Nguyen, P. V.
Metaplasticity of the late-phase of long-term
potentiation: a critical role for protein kinase A in
synaptic tagging. Eur. J. Neurosci. 23, 1784–1794
(2006).
84. Sajikumar, S., Navakkode, S. & Frey, J. U.
Identification of compartment- and process-specific
molecules required for “synaptic tagging” during long-
term potentiation and long-term depression in
hippocampal CA1. J. Neurosci. 27, 5068–5080
(2007).
© 2008 Nature Publishing Group
REVIEWS
85. Sajikumar, S., Navakkode, S., Sacktor, T. C. & Frey, J. U.
Synaptic tagging and cross-tagging: the role of protein
kinase Mζ in maintaining long-term potentiation but not
long-term depression. J. Neurosci. 25, 5750–5756
(2005).
86. Kauderer, B. S. & Kandel, E. R. Capture of a protein
synthesis-dependent component of long-term
depression. Proc. Natl Acad. Sci. USA 97,
13342–13347 (2000).
87. Sajikumar, S. & Frey, J. U. Late-associativity, synaptic
tagging, and the role of dopamine during LTP and LTD.
Neurobiol. Learn. Mem. 82, 12–25 (2004).
88. Govindarajan, A., Kelleher, R. J. & Tonegawa, S.
A clustered plasticity model of long-term memory
engrams. Nature Rev. Neurosci. 7, 575–583 (2006).
89. Sajikumar, S., Navakkode, S., Korz, V. & Frey, J. U.
Cognitive and emotional information processing:
protein synthesis and gene expression. J. Physiol.
584, 389–400 (2007).
90. Barco, A., Alarcon, J. M. & Kandel, E. R. Expression of
constitutively active CREB protein facilitates the late
phase of long-term potentiation by enhancing synaptic
capture. Cell 108, 689–703 (2002).
91. Woo, N. H. & Nguyen, P. V. Protein synthesis is
required for synaptic immunity to depotentiation.
J. Neurosci. 23, 1125–1132 (2003).
92. Akirav, I. & Richter-Levin, G. Priming stimulation in the
basolateral amygdala modulates synaptic plasticity in the
rat dentate gyrus. Neurosci. Lett. 270, 83–86 (1999).
93. Nakao, K., Matsuyama, K., Matsuki, N. & Ikegaya, Y.
Amygdala stimulation modulates hippocampal
synaptic plasticity. Proc. Natl Acad. Sci. USA 101,
14270–14275 (2004).
94. Frey, S., Bergado, J. A. & Frey, J. U. Modulation of late
phases of long-term potentiation in rat dentate gyrus
by stimulation of the medial septum. Neuroscience
118, 1055–1062 (2003).
95. Bergado, J. A., Frey, S., Lopez, J., Almaguer-Melian, W.
& Frey, J. U. Cholinergic afferents to the locus
coeruleus and noradrenergic afferents to the medial
septum mediate LTP-reinforcement in the dentate
gyrus by stimulation of the amygdala. Neurobiol.
Learn. Mem. 88, 331–341 (2007).
96. Zhang, W. & Linden, D. J. The other side of the
engram: experience-driven changes in neuronal
intrinsic excitability. Nature Rev. Neurosci. 4,
885–900 (2003).
97. Magee, J. C. & Johnston, D. Plasticity of dendritic
function. Curr. Opin. Neurobiol. 15, 334–342 (2005).
98. Marder, E. & Goaillard, J.‑M. Variability, compensation
and homeostasis in neuron and network function.
Nature Rev. Neurosci. 7, 563–574 (2006).
99. Kim, S. J. & Linden, D. J. Ubiquitous plasticity and
memory storage. Neuron 56, 582–592 (2007).
100. Sah, P. & Bekkers, J. M. Apical dendritic location of
slow afterhyperpolarization current in hippocampal
pyramidal neurons: implications for the integration of
long-term potentiation. J. Neurosci. 16, 4537–4542
(1996).
101. Blitzer, R. D., Wong, T., Nouranifar, R., Iyengar, R. &
Landau, E. M. Postsynaptic cAMP pathway gates early
LTP in hippocampal CA1 region. Neuron 15,
1403–1414 (1995).
102. Le Ray, D., De Sevilla, D. F., Porto, A. B., Fuenzalida, M.
& Buno, W. Heterosynaptic metaplastic regulation of
synaptic efficacy in CA1 pyramidal neurons of rat
hippocampus. Hippocampus 14, 1011–1025 (2004).
103. Kim, J., Jung, S.‑C., Clemens, A. M., Petralia, R. S. &
Hoffman, D. A. Regulation of dendritic excitability by
activity-dependent trafficking of the A‑type K+ channel
subunit Kv4.2 in hippocampal neurons. Neuron 54,
933–947 (2007).
104. Wang, Z. R., Xu, N. L., Wu, C. P., Duan, S. M. & Poo,
M. M. Bidirectional changes in spatial dendritic
integration accompanying long-term synaptic
modifications. Neuron 37, 463–472 (2003).
105. Mittmann, W. & Hausser, M. Linking synaptic
plasticity and spike output at excitatory and inhibitory
synapses onto cerebellar purkinje cells. J. Neurosci.
27, 5559–5570 (2007).
106. Freund, T. F. & Buzsaki, G. Interneurons of the
hippocampus. Hippocampus 6, 347–470 (1996).
107. Kullmann, D. M. & Lamsa, K. P. Long-term synaptic
plasticity in hippocampal interneurons. Nature Rev.
Neurosci. 8, 687–699 (2007).
108. Pitler, T. A. & Alger, B. E. Postsynaptic spike firing
reduces synaptic GABAA responses in hippocampal
pyramidal cells. J. Neurosci. 12, 4122–4132 (1992).
109. Wigstrom, H. & Gusstafsson, B. Facilitated induction of
long-lasting potentiation during blockade of inhibition.
Nature 301, 603–604 (1983).
REVIEWS
110. Kerr, D. S. & Abraham, W. C. Cooperative interactions
among afferents govern the induction of homosynaptic
long-term depression in the hippocampus. Proc. Natl
Acad. Sci. USA 92, 11637–11641 (1995).
111. Liu, Y. B., Disterhoft, J. F. & Slater, N. T. Activation of
metabotropic glutamate receptors induces long-term
depression of GABAergic inhibition in hippocampus.
J. Neurophysiol. 69, 1000–1004 (1993).
112. Marsicano, G. et al. The endogenous cannabinoid
system controls extinction of aversive memories.
Nature 418, 530–534 (2002).
113. Alger, B. E. Retrograde signaling in the regulation of
synaptic transmission: focus on endocannabinoids.
Prog. Neurobiol. 68, 247–286 (2002).
114. Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids
mediate retrograde signalling at hippocampal
synapses. Nature 410, 588–592 (2001).
115. Carlson, G., Wang, Y. & Alger, B. E. Endocannabinoids
facilitate the induction of LTP in the hippocampus.
Nature Neurosci. 5, 723–724 (2002).
116. Azad, S. C. et al. Circuitry for associative plasticity in
the amygdala involves endocannabinoid signaling.
J. Neurosci. 24, 9953–9961 (2004).
117. Chevaleyre, V. & Castillo, P. E. Endocannabinoid-
mediated metaplasticity in the hippocampus. Neuron
43, 871–881 (2004).
This paper characterized a novel mechanism of
metaplasticity, namely the endocannabinoid-
mediated long-term depression of GABA release.
118. Chevaleyre, V., Heifets, B. D., Kaeser, P. S., Sudhof,
T. C. & Castillo, P. E. Endocannabinoid-mediated long-
term plasticity requires cAMP/PKA signaling and
RIM1α. Neuron 54, 801–812 (2007).
119. Harvey, C. D. & Svoboda, K. Locally dynamic synaptic
learning rules in pyramidal neuron dendrites. Nature
450, 1195–1200 (2007).
120. Van Praag, H., Christie, B. R., Sejnowski, T. J. & Gage,
F. H. Running enhances neurogenesis, learning, and
long-term potentiation in mice. Proc. Natl Acad. Sci.
USA 96, 13427–13431 (1999).
121. Duffy, S. N., Craddock, K. J., Abel, T. & Nguyen, P. V.
Environmental enrichment modifies the PKA-dependence
of hippocampal LTP and improves hippocampus-
dependent memory. Learn. Mem. 8, 26–34 (2001).
122. Foster, T. C., Fugger, H. N. & Cunningham, S. G.
Receptor blockade reveals a correspondence between
hippocampal-dependent behavior and experience-
dependent synaptic enhancement. Brain Res. 871,
39–43 (2000).
123. Kim, J. J., Foy, M. R. & Thompson, R. F. Behavioral
stress modifies hippocampal plasticity through
N‑methyl‑d-aspartate receptor activation. Proc. Natl
Acad. Sci. USA 93, 4750–4753 (1996).
124. Garcia, R., Musleh, W., Tocco, G., Thompson, R. F. &
Baudry, M. Time-dependent blockade of STP and LTP
in hippocampal slices following acute stress in mice.
Neurosci. Lett. 233, 41–44 (1997).
125. Maggio, N. & Segal, M. Striking variations in
corticosteroid modulation of long-term potentiation
along the septotemporal axis of the hippocampus.
J. Neurosci. 27, 5757–5765 (2007).
126. Kim, J. J. & Yoon, K. S. Stress: metaplastic effects in the
hippocampus. Trends Neurosci. 21, 505–509 (1998).
127. Diamond, D. M., Park, C. R. & Woodson, J. C. Stress
generates emotional memories and retrograde
amnesia by inducing an endogenous form of
hippocampal LTP. Hippocampus 14, 281–291 (2004).
128. Abraham, W. C. Stress-related phenomena.
Hippocampus 14, 675–676 (2004).
129. Shors, T. J. & Thompson, R. F. Acute stress impairs (or
induces) synaptic long-term potentiation (LTP) but
does not affect paired-pulse facilitation in the stratum-
radiatum of rat hippocampus. Synapse 11, 262–265
(1992).
130. Sacchetti, B. et al. Long-lasting hippocampal
potentiation and contextual memory consolidation.
Eur. J. Neurosci. 13, 2291–2298 (2001).
131. Sacchetti, B., Scelfo, B., Tempia, F. & Strata, P. Long-
term synaptic changes induced in the cerebellar cortex
by fear conditioning. Neuron 42, 973–982 (2004).
132. Sacchetti, B. et al. Time-dependent inhibition of
hippocampal LTP in vitro following contextual fear
conditioning in the rat. Eur. J. Neurosci. 15, 143–150
(2002).
133. Kirkwood, A., Rioult, M. G. & Bear, M. F. Experience-
dependent modification of synaptic plasticity in visual
cortex. Nature 381, 526–528 (1996).
134. Philpot, B. D., Espinosa, J. S. & Bear, M. F. Evidence
for altered NMDA receptor function as a basis for
metaplasticity in visual cortex. J. Neurosci. 23,
5583–5588 (2003).
398 | may 2008 | volume 9 www.nature.com/reviews/neuro
135. Quinlan, E. M., Olstein, D. H. & Bear, M. F.
Bidirectional, experience-dependent regulation of
N‑methyl‑D-aspartate receptor subunit composition in
the rat visual cortex during postnatal development.
Proc. Natl Acad. Sci. USA 96, 12876–12880 (1999).
136. Quinlan, E. M., Philpot, B. D., Huganir, R. L. & Bear,
M. F. Rapid, experience-dependent expression of
synaptic NMDA receptors in visual cortex in vivo.
Nature Neurosci. 2, 352–357 (1999).
137. Bellone, C. & Nicoll, R. A. Rapid bidirectional switching
of synaptic NMDA receptors. Neuron 55, 779–785
(2007).
138. Erreger, K., Dravid, S. M., Banke, T. G., Wyllie, D. J. A.
& Traynelis, S. E. Subunit-specific gating controls rat
NR1/NR2A and NR1/NR2B NMDA channel kinetics
and synaptic signalling profiles. J. Physiol. 563,
345–358 (2005).
139. Philpot, B. D., Cho, K. K. A. & Bear, M. F. Obligatory
role of NR2A for metaplasticity in visual cortex.
Neuron 53, 495–502 (2007).
This work provided an elegant demonstration that
the subunit composition of NMDARs is critical for
experience-dependent alterations in plasticity
thresholds in the visual cortex.
140. Disterhoft, J. F., Golden, D. T., Read, H. R., Coulter,
D. A. & Alkon, D. L. AHP reduction in rabbit
hippocampal neurons during conditioning correlate
with acquisition of the learned response. Brain Res.
462, 118–125 (1988).
141. Alkon, D. L. Voltage-dependent calcium and potassium
ion conductances: a contingency mechanism for an
associative learning model. Science 205, 810–816
(1979).
142. Kandel, E. R. & Schwartz, J. H. Molecular biology of
learning: modulation of transmitter release. Science
218, 433–443 (1982).
143. Moyer, J. R. Jr, Thompson, L. T. & Disterhoft, J. F.
Trace eyeblink conditioning increases CA1 excitability
in a transient and learning-specific manner.
J. Neurosci. 16, 5536–5546 (1996).
144. Oh, M. M., Kuo, A. G., Wu, W. W., Sametsky, E. A. &
Disterhoft, J. F. Watermaze learning enhances
excitability of CA1 pyramidal neurons.
J. Neurophysiol. 90, 2171–2179 (2003).
145. Saar, D., Grossman, Y. & Barkai, E. Reduced after-
hyperpolarization in rat piriform cortex pyramidal
neurons is associated with increased learning
capability during operant conditioning. Eur. J.
Neurosci. 10, 1518–1523 (1998).
146. Cohen-Matsliah, S. I., Brosh, I., Rosenblum, K. &
Barkai, E. A novel role for extracellular signal-
regulated kinase in maintaining long-term memory-
relevant excitability changes. J. Neurosci. 27,
12584–12589 (2007).
147. Brosh, I., Rosenblum, K. & Barkai, E. Learning-
induced modulation of SK channels-mediated effect
on synaptic transmission. Eur. J. Neurosci. 26,
3253–3260 (2007).
148. Lebel, D., Grossman, Y. & Barkai, E. Olfactory learning
modifies predisposition for long-term potentiation and
long-term depression induction in the rat piriform
(olfactory) cortex. Cereb. Cortex 11, 485–489 (2001).
149. Quinlan, E. M., Lebel, D., Brosh, I. & Barkai, E.
A molecular mechanism for stabilization of learning-
induced synaptic modifications. Neuron 41, 185–192
(2004).
150. Disterhoft, J. F. & Oh, M. M. Learning, aging and
intrinsic neuronal plasticity. Trends Neurosci. 29,
587–599 (2006).
151. Zelcer, I. et al. A cellular correlate of learning-induced
metaplasticity in the hippocampus. Cereb. Cortex 16,
460–468 (2006).
This paper provided clear evidence for a type of
learning-induced metaplasticity that promotes
subsequent learning of other behaviours, mediated
by regulation of the sAHP.
152. Levenson, J. M. et al. Regulation of histone acetylation
during memory formation in the hippocampus. J. Biol.
Chem. 279, 40545–40559 (2004).
153. Levenson, J. M. et al. Evidence that DNA (cytosine‑5)
methyltransferase regulates synaptic plasticity in the
hippocampus. J. Biol. Chem. 281, 15763–15773
(2006).
154. Miller, C. A., Campbell, S. L. & Sweatt, J. D. DNA
methylation and histone acetylation work in concert to
regulate memory formation and synaptic plasticity.
Neurobiol. Learn. Mem. 17 Sep 2007 [epub ahead of
print].
155. Clem, R. L., Celikel, T. & Barth, A. L. Ongoing in vivo
experience triggers synaptic metaplasticity in the
neocortex. Science 319, 101–104 (2008).
© 2008 Nature Publishing Group
156. Oddo, S. et al. Triple-transgenic model of Alzheimer’s
disease with plaques and tangles: intracellular Aβ and
synaptic dysfunction. Neuron 39, 409–421 (2003).
This paper provided an important demonstration
that sensory experience can cause NMDAR-
dependent LTP. The LTP saturates owing to an
NMDAR-dependent inhibition of additional mGluR-
mediated potentiation.
157. Albensi, B. C. & Janigro, D. Traumatic brain injury and
its effects on synaptic plasticity. Brain Inj. 17,
653–663 (2003).
158. Schwarzbach, E., Bonislawski, D. P., Xiong, G. &
Cohen, A. S. Mechanisms underlying the inability to
induce area CA1 LTP in the mouse after traumatic
brain injury. Hippocampus 16, 541–550 (2006).
159. Wang, S., Kee, N., Preston, E. & Wojtowicz, J. M.
Electrophysiological correlates of neural plasticity
compensating for ischemia-induced damage in the
hippocampus. Exp. Brain Res. 165, 250–260 (2005).
160. Goussakov, I. V., Fink, K., Elger, C. E. & Beck, H.
Metaplasticity of mossy fiber synaptic transmission
involves altered release probability. J. Neurosci. 20,
3434–3441 (2000).
161. Kleschevnikov, A. M. et al. Hippocampal long-term
potentiation suppressed by increased inhibition in the
Ts65Dn mouse, a genetic model of Down syndrome.
J. Neurosci. 24, 8153–8160 (2004).
162. Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear,
M. F. Altered synaptic plasticity in a mouse model of
fragile X mental retardation. Proc. Natl Acad. Sci. USA
99, 7746–7750 (2002).
163. Picconi, B. et al. Pathological synaptic plasticity in
the striatum: implications for Parkinson’s disease.
Neurotoxicology 26, 779–783 (2005).
164. Kung, V. W. S., Hassam, R., Morton, A. J. & Jones, S.
Dopamine-dependent long term potentiation in the
dorsal striatum is reduced in the R6/2 mouse model of
Huntington’s disease. Neuroscience 146, 1571–1580
(2007).
165. Turrigiano, G. G. & Nelson, S. B. Homeostatic
plasticity in the developing nervous system. Nature
Rev. Neurosci. 5, 97–107 (2004).
166. Thiagarajan, T. C., Lindskog, M. & Tsien, R. W.
Adaptation to synaptic inactivity in hippocampal
neurons. Neuron 47, 725–737 (2005).
167. Slutsky, I., Sadeghpour, S., Li, B. & Liu, G. S.
Enhancement of synaptic plasticity through chronically
reduced Ca2+ flux during uncorrelated activity. Neuron
44, 835–849 (2004).
168. Eid, T., Kovacs, I., Spencer, D. D. & de Lanerolle, N. C.
Novel expression of AMPA-receptor subunit GluR1 on
mossy cells and CA3 pyramidal neurons in the human
epileptogenic hippocampus. Eur. J. Neurosci. 15,
517–527 (2002).
169. He, H. Y., Hodos, W. & Quinlan, E. M. Visual
deprivation reactivates rapid ocular dominance
plasticity in adult visual cortex. J. Neurosci. 26,
2951–2955 (2006).
170. Hofer, S. B., Mrsic-Flogel, T. D., Bonhoeffer, T. &
Hubener, M. Prior experience enhances plasticity in
adult visual cortex. Nature Neurosci. 9, 127–132
(2006).
This important paper demonstrated that the adult
visual cortex is capable of substantial experience-
dependent plasticity if it has previously been
primed by brief exposure to altered visual
experience.
171. He, H.‑Y., Ray, B., Dennis, K. & Quinlan, E. M.
Experience-dependent recovery of vision following
chronic deprivation amblyopia. Nature Neurosci. 10,
1134–1136 (2007).
This paper provided a clinically important
demonstration that amblyopia that has been
induced by MD can be reversed if the cortex is first
primed by putting animals in a dark environment
just prior to the reversal procedures.
172. Sale, A. et al. Environmental enrichment in adulthood
promotes amblyopia recovery through a reduction of
intracortical inhibition. Nature Neurosci. 10,
679–681 (2007).
173. Ullal, G. R., Ninchoji, T. & Uemura, K. Low frequency
stimulation induces an increase in after-discharge
thresholds in hippocampal and amygdaloid kindling.
Epilepsy Res. 3, 236–247 (1989).
174. Hesp, B. R., Clarkson, A. N., Sawant, P. M. & Kerr,
D. S. Domoic acid preconditioning and seizure
induction in young and aged rats. Epilepsy Res. 76,
103–112 (2007).
175. Gidday, J. M. Cerebral preconditioning and ischaemic
tolerance. Nature Rev. Neurosci. 7, 437–448
(2006).

176. Schaller, B. & Graf, R. Cerebral ischemic
preconditioning. J. Neurol. 249, 1503–1511 (2002).
177. Dirnagl, U., Simon, R. P. & Hallenbeck, J. M. Ischemic
tolerance and endogenous neuroprotection. Trends
Neurosci. 26, 248–254 (2003).
178. Thiagarajan, T. C., Lindskog, M., Malgaroli, A. & Tsien,
R. W. LTP and adaptation to inactivity: overlapping
mechanisms and implications for metaplasticity.
Neuropharmacology 52, 156–175 (2007).
179. Fusi, S., Drew, P. J. & Abbott, L. F. Cascade models of
synaptically stored memories. Neuron 45, 599–611
(2005).
This paper detailed an innovative network model
that incorporates multiple metaplastic states into
the functionality of the synapses so as to prolong
the duration of memories stored in the network.
180. Fusi, S. & Abbott, L. F. Limits on the memory storage
capacity of bounded synapses. Nature Neurosci. 10,
485–493 (2007).
181. Montgomery, J. M. & Madison, D. V. Discrete synaptic
states define a major mechanism of synapse plasticity.
Trends Neurosci. 27, 744–750 (2004).
182. Ward, B. et al. State-dependent mechanisms of LTP
expression revealed by optical quantal analysis.
Neuron 52, 649–661 (2006).
183. Yang, X. D. & Faber, D. S. Initial synaptic efficacy
influences induction and expression of long-term
changes in transmission. Proc. Natl Acad. Sci. USA
88, 4299–4303 (1991).
184. Barrionuevo, G., Schottler, F. & Lynch, G. The effects of
repetitive low-frequency stimulation on control and
nature reviews | neuroscience volume 9 | may 2008 | 399
‘potentiated’ synaptic responses in the hippocampus.
Life Sci. 27, 2385–2391 (1980).
185. Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F.
& Huganir, R. L. Regulation of distinct AMPA receptor
phosphorylation sites during bidirectional synaptic
plasticity. Nature 405, 955–959 (2000).
186. Benuskova, L. & Abraham, W. STDP rule endowed
with the BCM sliding threshold accounts for
hippocampal heterosynaptic plasticity. J. Comp.
Neurosci. 22, 129–133 (2007).
187. Benuskova, L., Diamond, M. E. & Ebner, F. F. Dynamic
synaptic modification threshold: computational model of
experience-dependent plasticity in adult rat barrel cortex.
Proc. Natl Acad. Sci. USA 91, 4791–4795 (1994).
188. Izhikevich, E. M. & Desai, N. S. Relating STDP to
BCM. Neural Comput. 15, 1511–1523 (2003).
189. Bear, M. F., Cooper, L. N. & Ebner, F. F. A physiological
basis for a theory of synapse modification. Science
237, 42–48 (1987).
190. Shouval, H. Z., Bear, M. F. & Cooper, L. N. A unified
model of NMDA receptor-dependent bidirectional
synaptic plasticity. Proc. Natl Acad. Sci. USA 99,
10831–10836 (2002).
191. Shouval, H. Z., Castellani, G. C., Blais, B. S., Yeung,
L. C. & Cooper, L. N. Converging evidence for a
simplified biophysical model of synaptic plasticity. Biol.
Cybern. 87, 383–391 (2002).
192. Yeung, L. C., Shouval, H. Z., Blais, B. S. & Cooper,
L. N. Synaptic homeostasis and input selectivity follow
from a calcium-dependent plasticity model. Proc. Natl
Acad. Sci. USA 101, 14943–14948 (2004).
© 2008 Nature Publishing Group
REVIEWS
Acknowledgements
Preparation of this Review was assisted by a James Cook
Fellowship from the Royal Society of New Zealand.
Metaplasticity research in the author’s laboratory has been
supported by grants from the Health Research Council of New
Zealand, the New Zealand Marsden Fund and the University
of Otago Research Committee. I thank M. Bear for many
years of discussion and collaboration on metaplasticity topics.
I thank D. Ireland, J. Wagner and E. Quinlan for comments on
an earlier version of this manuscript.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
brain-derived neurotrophic factor | αCaMKII | elongation
factor 1α | elongation factor 2 | ERK1 | ERK2 | mTOR |
neurogranin | p38 MAPK | poly‑A binding protein 1 |
ribosomal protein S6
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Alzheimer’s disease | Down syndrome | Fragile X-linked
mental retardation syndrome | Huntington’s disease |
Parkinson’s disease
FURTHER INFORMATION
Wickliffe Abraham’s homepage:
http://psy.otago.ac.nz/staff/abraham.html
All links are active in the online pdf